NM_016507.4:c.3424T>A

CDK12 · NP_057591.2:p.(Ser1142Thr) · NM_016507.4

GRCh37: chr17:37682233 T>A · GRCh38: chr17:39525980 T>A

Gene: CDK12 Transcript: NM_016507.4

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

CDK12

Transcript

NM_016507.4

Protein

NP_057591.2:p.(Ser1142Thr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_016507.4:c.3424T>A (p.Ser1142Thr) is a missense variant in CDK12 exon 13.

This variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at moderate strength.

Multiple lines of computational evidence predict a benign effect: REVEL score 0.142, BayesDel score -0.294, and SpliceAI max delta 0.00, satisfying BP4 at supporting benign strength.

The variant is absent from ClinVar and COSMIC; no functional data, segregation data, or case-control data are available.

PVS1 is not applicable as this is a missense variant, not a predicted null variant.

Overall, one moderate pathogenic criterion (PM2) is met, and one supporting benign criterion (BP4) is met. Per the ACMG/AMP 2015 combination rules, a single moderate criterion with a supporting benign criterion results in a classification of Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_016507.4:c.3424T>A is a missense variant (p.Ser1142Thr) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per the ClinGen SVI PVS1 decision tree (PMC6185798).	pvs1_generic_framework
PS1	Not met	No established pathogenic variant with the same amino acid change (p.Ser1142Thr) has been reported in ClinVar; this variant is absent from all ClinVar records.	clinvar
PS2	Not met	No de novo occurrence with confirmed parentage has been reported for this variant in any available source.
PS3	Not met	No variant-specific functional data are available. REVEL score is 0.142 and BayesDel score is -0.294, both consistent with a benign in silico prediction. OncoKB reports unknown oncogenic effect with no variant-specific reviewed functional evidence.	revel bayesdel oncokb
PS4	Not met	No case-control or prevalence data are available comparing affected individuals to controls for this variant.
PS5	N/A	PS5 is not defined in the ACMG/AMP 2015 framework employed for this case. No alternate framework or evidence source provides an applicable PS5 rule.
PM1	Not met	Residue Ser1142 lies in the C-terminal region of CDK12, well outside the characterized kinase domain (approx. residues 719-983). This position is not within a statistically significant mutational hotspot per cancerhotspots.org, and no variant-specific or residue-specific functional domain evidence is available in the case materials to support PM1.
PM2	Met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the PM2 criterion for absence from large population databases (allele frequency < 0.1% in non-VCEP generic ACMG framework).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same codon (Ser1142) has been identified in ClinVar. The automated PM5 candidate search returned zero same-residue candidates.	pm5_candidates clinvar
PM6	Not met	No de novo occurrence (with or without confirmed parentage) has been reported for this variant in any available clinical or literature source.
PP1	Not met	No segregation data are available for this variant in affected families.
PP2	Not met	Missense constraint metrics for CDK12 are not available (HCI prior not found); no evidence that CDK12 has a low rate of benign missense variation. PP2 cannot be applied without supporting constraint data.
PP3	Not met	Multiple computational tools predict a benign effect: REVEL score 0.142 (well below the 0.5 pathogenic threshold), BayesDel score -0.294 (negative, consistent with benign), and SpliceAI max delta 0.00 (no predicted splicing impact). These lines of evidence do not support pathogenicity.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history information is available for this case to evaluate phenotypic specificity.
PP5	Not met	This variant is absent from ClinVar; no reputable source has reported it as pathogenic. PP5 cannot be applied without a ClinVar entry classified as pathogenic/likely pathogenic by a qualified submitter.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 requires an allele frequency > 5% in any general population, which is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from all population databases. BS1 requires an allele frequency greater than expected for the disorder (> 0.3% in non-VCEP generic ACMG framework), which is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	This variant has not been observed in any healthy adult individuals in gnomAD. BS2 requires observation in healthy adults for a fully penetrant disorder, which cannot be satisfied by absence.
BS3	Not met	No well-established functional studies demonstrate a benign effect for this variant. Computational predictions (REVEL 0.142, BayesDel -0.294) are suggestive but do not constitute the well-established functional evidence required for BS3.
BS4	Not met	No segregation data are available to evaluate non-segregation with disease.
BP1	Not met	CDK12 is not established as a gene where only truncating variants cause disease. Germline CDK12 variants of multiple types (including missense) are reported in association with prostate cancer, and the mechanism is not exclusively loss-of-function by truncation.	pvs1_gene_context
BP2	Not met	No data are available regarding observation of this variant in trans with a known pathogenic variant.
BP4	Met	Multiple lines of computational evidence suggest no deleterious impact: REVEL score 0.142 (well below pathogenic threshold), BayesDel score -0.294 (negative, consistent with benign), and SpliceAI max delta score 0.00 (no predicted splicing alteration). This satisfies BP4 as multiple independent in silico predictors concur on a benign effect.	revel bayesdel spliceai
BP5	Not met	This variant is absent from ClinVar; no reputable source has reported it as benign. BP5 cannot be applied without evidence that an alternate molecular basis explains disease in a case harboring this variant.
BP6	Not met	This variant is absent from ClinVar; no reputable source has reported it as benign or likely benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splicing impact. NM_016507.4:c.3424T>A is a missense variant (p.Ser1142Thr), not a synonymous variant.
BP3	N/A	BP3 applies to in-frame insertions or deletions in repetitive regions. This is a single-nucleotide substitution, not an indel.
PM3	N/A	PM3 applies to recessive disorders. CDK12-associated disease is not recessively inherited.
PM4	N/A	PM4 applies to protein-length-changing variants (indels, stop-loss). This is a single-nucleotide missense substitution.

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